Fragile X syndrome is the most frequent inherited form of metal retardation in humans. The absence of the functional product of the FMR1 gene, FMRP, is believed to be responsible for the mental retardation and associated phenotype. The precise function of FMRP is obscure although recent progress has found it to be an RNA-binding protein associated with translating ribosomes. Such data, therefore may imply that the absence of FMRP influences translation and that fragile X syndrome results from an abnormality in protein synthesis. This proposal aims to understand the normal function of FMRP in translation and the consequence of its absence on protein synthesis. Three proposed specific aims are: 1) to characterize the dynamic association of FMRP with translation machinery. 2) to determine the influence of FMRP on translation. 3) to characterize the FMRP-ribosome association in brain neuron somatal-dendritic compartments, and to compare translation activity in normal and fmr1 knockout mouse brain. These studies will address the function and influence of FMRP in the normal state as well as in cell lacking FMRP in fragile X syndrome. The experiments proposed should further illuminate the normal function of FMRP and how its absence leads to fragile X syndrome.